Nec349943.indd
Original PaperNephron Clin Pract 2012;122:75–79 Received: November 27, 2012 Accepted: February 12, 2013 Published online: M arch 28, 2013 Uraemic Pruritus: Relief of Itching by
Gabapentin and Pregabalin
Hugh Rayner Jyoti Baharani Steve Smith Vijayan Suresh Indranil Dasgupta Heart of England NHS Foundation Trust, Birmingham , UK Key Words
itch severity out of 10 reduced from 8 to 1. Conclusions: Ga-
Uraemia · Pruritus · Itch · Gabapentin · Pregabalin · Dialysis · bapentin or pregabalin relieved itching in 85% of 71 con- Chronic kidney disease secutively treated CKD patients. Patients should be advised about side effects and the drug initiated at a low dose. Pa-tients intolerant of gabapentin may tolerate pregabalin. Abstract
Copyright 2013 S. Karger AG, Basel Background: Pruritus (skin irritation or itching) is common
in patients with chronic kidney disease (CKD) stages 4 and
5. It is associated with disrupted sleep, reduced quality of
Introduction
life, depression and increased mortality. A video of a patient
describing the symptoms is at vimeo.com/49458473. Meth-
Pruritus (skin irritation or itching) is common in pa- ods: We used gabapentin or pregabalin in 71 consecutive
tients with chronic kidney disease (CKD) stages 4 and 5. patients, 82% male. 25 had CKD stage 4 or 5, median eGFR For many patients, the symptoms are much more than = 17, range 9–30; 40 were on haemodialysis; 6 on peritoneal intermittent irritations relieved by a satisfying scratch. dialysis. Median itch severity score out of 10 = 8, range 6–10; 32% of haemodialysis (HD) patients are moderately or median duration of itching = 6 months, range 0.5–240. Se- very much bothered by itchiness and 10% extremely rum calcium ≤ 2.60 mmol/l ( ≤ 10.4 mg/dl) in 87% patients, bothered [1] . HD patients with moderate or severe itch phosphate ≤ 1.8 mmol/l ( ≤ 5.6 mg/dl) in 75%. 63% had used are significantly more likely to feel drained or depressed antihistamines and not gained relief. Starting dose of gaba- and have a 17% higher mortality risk [1] , statistically as- pentin 100 mg after dialysis or daily. Patients intolerant of sociated with the quality of sleep [1] . A patient's descrip- gabapentin were offered pregabalin, starting dose 25 mg tion of these symptoms and their impact is at vimeo.
after dialysis or daily. Results: Gabapentin relieved itching
in 47 patients (66%). A video of a patient describing the ef- HD patients with itching and pain due to diabetic neu- fect is at vimeo.com/49455976. 26 patients (37%) suffered ropathy were found to be relieved of both symptoms by side effects from gabapentin. Of 21 patients who stopped gabapentin [2, 3] . This suggests that GABA-dependent gabapentin due to side effects, 16 started pregabalin. Pre- C-terminal afferent nerve fibres mediate uraemic pruri- gabalin relieved itching in 13 patients (81%). In total, gaba- tus. Gabapentin is an analogue of the inhibitory neu- pentin or pregabalin relieved itching in 60 patients (85%), rotransmitter gaba-aminobutyric acid, GABA. Pregaba- median follow-up 2 months (range 1–8 months). Median lin (Lyrica ® ) is a similar, more potent drug. They are 2013 S. Karger AG, Basel Dr. Hugh C. Rayner Heart of England NHS Foundation Trust E-Mail [email protected] Bordesley Green East www.karger.com/nec Birmingham B9 5SS (UK) E-Mail hugh.rayner @ heartofengland.nhs.uk 65.175.149.156 - 1/5/2014 4:01:06 AM mainly used in the treatment of epilepsy and neuropathic months. Patients were severely affected by itching, 87% pain. They are eliminated by renal excretion as unchanged having sleep disturbance and 66% making themselves drug. Common side effects include dizziness and drows- bleed from scratching. Details of their demographics, symptoms, previous treatment, dosage and response to A randomised double-blind placebo controlled cross- gabapentin are given in table 1 .
over trial of gabapentin in 25 HD patients aged 32–77 63% had tried antihistamines with limited or no effect. years showed a dramatic reduction in the severity of itch One had gained no benefit from a course of UV therapy. [2] . Similar results in HD patients have been reported in The majority had serum calcium (corrected for serum al-two subsequent trials [4, 5] and a small case series [3] . bumin) and phosphate levels below the upper limit of rec- There have been two reports of relief of renal itch with ommended ranges (87% calcium <2.60 mmol/l, <10.4 pregabalin [6, 7] .
mg/dl; 75% phosphate <1.8 mmol/l, <5.6 mg/dl).
We report our experience of using gabapentin and 47 (66%) gained relief of itch from gabapentin. Median pregabalin to treat pruritus in a cohort of patients with itch severity was 1 (range 0–6) after median treatment CKD stages 4 and 5 from a wide age range, including duration of 2 months (range 1–8).
those receiving peritoneal dialysis and HD.
The following are verbatim reports from patients whose itching was relieved: ‘You prescribed gabapentin and she took one 100 mg capsule on Friday evening after dialysis. She felt drowsy after half an hour The Heart of England NHS Foundation Trust provides ne- and then had the most remarkable 2 days of relief from the itching phrology services to the population of approximately 800,000 in I have seen for many years. On Monday some symptoms re-ap- East Birmingham and the surrounding area. This is a socioeco- peared… she [took] another capsule [on] Monday evening after nomically and ethnically diverse community. In December 2012, dialysis. The relief was the same, with another peaceful and undis- the service was treating 407 patients on HD and 47 on peritoneal turbed night's sleep (for both of us!). We cannot thank you enough dialysis. 450 patients were receiving care for CKD stages 4 and 5 for prescribing this medicine. It has given E peace of mind, the prior to renal replacement therapy. Subjects with itching were strain has dropped from her face and she is much more positive identified during routine consultations.
about her condition and treatment.' Patient E.
Itch severity was assessed before treatment using a scale rang- They are ‘magic pills'. I'm a ‘new man'. ‘Let other people who ing from 0 to 10 where 10 was the most severe itch imaginable. suffer from itching try this.' Patient D.
Patients whose itching was sufficiently troublesome, persistent ‘After 2 h the itching went off like a light switch.' ‘I am a differ- and unrelieved by simple emollients or antihistamines were of- ent man.' Patient J.
fered gabapentin treatment. Patients were advised that gabapentin ‘I'm still itching in the mornings when I get up but once I have was not licenced in the UK for this indication and were warned of my tablet of gabapentin I stop itching for the rest of the day, until possible side effects, particularly drowsiness. Patient gave verbal late evening and perhaps once during the night. But Wow I've been consent to be included in this report.
catching up on my sleep! Therefore, I have had so much more en- Gabapentin was started at 100 mg once daily for CKD and peri- ergy during the day and feel my depression lifting!' Patient V.
toneal dialysis (PD) patients and at 100 mg after dialysis for HD ‘I have found I need to take a tablet during the weekend – patients. Patients adjusted the dose regimen according to their later Saturday or Sunday morning as the itching starts to return symptoms in collaboration with their physician. Verbatim de- so a dosage of 100 mg 4 times weekly seems appropriate for me. scriptions of quality of life before and during gabapentin treatment I do notice that towards the end of the dialysis session I am start- were noted. One patient gave written consent for an interview to ing to itch so glad to take the tablet once the session has ended.' be video recorded and made available via the Internet.
Patients who were unable to continue gabapentin due to side effects were offered pregabalin, starting at 25 mg once daily for A video of one patient's experience of using gabapen- CKD and PD patients and 25 mg after dialysis for HD patients.
Patients were prescribed gabapentin or pregabalin as an open tin can be seen at vimeo.com/49455976.
label drug. There was no placebo or control group.
Twenty-six patients (37%) suffered side effects from gabapentin: over-sedation (12), dizziness (6), tight chest/breathlessness (3), shaking limbs (2), vomiting (2), blotchy rash (2), nightmares (1), cramps (1), hair loss (1), low BP (1), incontinence (1); some patients had multiple side effects. 24 (34%) stopped gabapentin: 3 due to lack of Results on 71 consecutive patients with severe itching effect on itching, 21 due to side effects.
(score ≥ 6/10) started on gabapentin since February 2012 Of the 21 who stopped gabapentin due to side effects, are presented. Itching had been present for a median of 6 16 were treated with pregabalin ( table 2 ). 13 (81%) gained Nephron Clin Pract 2012;122:75–79 Rayner/Baharani/Smith/Suresh/Dasgupta 65.175.149.156 - 1/5/2014 4:01:06 AM Table 1. Details of patients treated with gabapentin
Number of patients Age, median (range), years eGFR, median (range), ml/min/1.73 m2 Duration of RRT, median (range), months Serum Ca, albumin-corrected, median (range), mg/dl, mmol/l 9.44 (8.60–10.48) 9.78 (7.16–11.52) 10.32 (9.36–10.40) 2.36 (2.15–2.62) 2.45 (1.79–2.88) 2.59 (2.34–2.68) Serum phosphate, median (range), mg/dl, mmol/l 4.37 (3.00–6.04) 4.75 (2.2–8.85) 4.58 (2.91–5.73) 1.41 (0.97–1.95) 1.54 (0.71–2.86) 1.49 (0.94–1.86) PTH, median (range), pg/ml Duration of itching, median (range), months Severity of itch, median (max = 10) Sleep disturbance, yes (%) Bleeding from scratching, yes (%) Previous antihistamines, yes (%) Itch response: (1) side effects, gabapentin stopped (2) no reduction of itch, gabapentin stopped(3) significant reduction of itch: n Final dose of gabapentin 13@100 mg o.d.
13@100 mg after dialysis 3@100 mg o.d.
4@100 mg b.d.
2@300 mg after dialysis 1@200 mg o.d.
5@200 mg o.d.
1@400 mg after dialysis 1@300 mg o.d.
2@300 mg o.d.
1@200 mg 2 weekly 6@200 mg daily5@300 mg daily1@400 mg daily1@900 mg daily Length of follow-up, median (range), months, Table 2. Details of patients treated with pregabalin
Number of patients Itch response: (1) side effects, pregabalin stopped (2) no reduction of itch, pregabalin stopped (3) significant reduction of itch: n Final dose of pregabalin 2@25 mg o.d.
1@25 mg after dialysis 1@25 mg o.d.
1@50 mg o.d.
2@25 mg o.d.
1@25 mg b.d.
2@75 mg o.d.
3@50 mg o.d.
1@50 mg o.d.
1@75 mg b.d.
Length of follow-up, median (range), months relief of itch from pregabalin. Median itch severity was 2 Combining both treatments, 60 of the 71 patients (range 0–5) after median treatment duration of 2.5 (85%) gained significant relief of their itch and continued months (range 1–4). 3 stopped pregabalin: 1 due to lack taking the tablets. For most, the effect was noticeable after of effect on itching, 2 due to side effects (oversedation in taking the first one or two doses or after an increase in both).
Gabapentin and Pregabalin Relieve Renal Nephron Clin Pract 2012;122:75–79 65.175.149.156 - 1/5/2014 4:01:06 AM No significant attenuation of the effect was reported. effective apart from their mild sedative effect. The pa- Two patients' itching returned when gabapentin was tients' description of renal itch differs from histamine-stopped because of supply problems; restarting it relieved mediated urticaria; renal itch is felt below the surface of the itching again. Four patients stopped taking gabapen- tin or pregabalin and remained free of itch.
Gabapentin also has been shown to relieve itching in Relief of itch was achieved in some patients with skin controlled trials involving patients with itch due to burns conditions associated with itching. One had pruritus and IL-2 treatment [9, 10] but not cholestasis [11] .
nodularis and 2 had chronic idiopathic urticaria. One pa- In the current prospective study of 71 consecutively tient with chronic eczema on the head and neck gained treated patients, 85% of patients treated with gabapentin complete relief of itching on the limbs and partial relief in or pregabalin gained substantial or complete relief from eczematous regions.
their itching whilst taking the drug. As this was not a ran- Six patients had improvement in pain conditions. Pe- domised placebo-controlled study, it cannot be proved ripheral neuropathic pain was relieved in 3 patients, se- that the drug was responsible for the effects reported. vere headaches and neck pain improved in 1 and joint However, the degree of reduction in itch was consistent pains and phantom limb pain improved in 1 each.
with previous placebo-controlled trials. Furthermore, pa-tients reported a clear dose-response relationship be-tween gabapentin/pregabalin and itch severity and titrat- Discussion
ed their treatment according to the response. Four pa-tients stopped the drug without the itch returning, This is the largest cohort study to date on the use of consistent with marked fluctuation in the severity of itch- gabapentin and pregabalin to treat severe itching in a ing week-to-week in some patients described in a detailed population of patients with CKD stage 4 and 5, including longitudinal study [12] .
those on HD and PD.
In the current study, 30% of patients experienced sig- Healthcare professionals may underestimate the im- nificant side effects with gabapentin and 12% with prega- pact of itching on the lives of some patients with CKD. balin, most commonly oversedation. It was not possible The unremitting symptoms stop the patient from relax- to predict which patients would suffer side effects. In the ing or sleeping. Patients and their partners become previous randomised trial of gabapentin [3] side effects drained and depressed. Two patients' lives were so affect- were mild to moderate and usually subsided within 7 ed by itch that they considered stopping HD: ‘It controls days. None of the patients in that trial dropped out. Pa-my life; it drives me mad.' A vivid description by one af- tients in our study may have been more prone to adverse fected patient is at vimeo.com/49458473.
effects due to greater age and comorbidity.
Itching is commonly attributed to high levels of serum Gabapentin and pregabalin should be started cau- calcium or phosphate. This can lead to a focus on inten- tiously with close feedback between physician and pa- sifying diet and phosphate binders to treat itch. Our ex- tient. We routinely started with 100 mg gabapentin after perience confirms data from the DOPPS showing that dialysis for HD patients or once daily at night in CKD and the mean values in patients with moderate or severe itch PD patients. Others have also found this to be a more ap-were only very slightly increased, 0.25 and 0.04 mg/dl propriate starting dose than the 300 mg used in the orig-(0.08 and 0.01 mmol/l), respectively [1] . The association inal RCT [4, 5] . The starting dose of pregabalin was 25 with high serum calcium and phosphate may not be mg. The effects of the drug were noticed after one or a few causal.
doses, allowing rapid dose adjustment. Patients should be The marked male predominance of patients with itch warned about possible sedation and dizziness. Patients in this series (82%) is consistent with the DOPPS study of with mobility difficulties or at risk of falls should be su- HD patients [1] . It is not known why males are more af- pervised for at least 12–24 h after the first dose.
Some patients had pain syndromes as well as itch and The available treatments for uraemic pruritus have gained relief of both symptoms. Relief of itch by gabapen- been recently reviewed in detail [8] . Antihistamines are tin in patients with peripheral neuropathic pain was the commonly used based upon their effect on urticarial itch. clue that led Gunal et al. [2] to carry out the initial ran- However, there have been no well-conducted ran- domised controlled trial. A recent study has shown simi- domised controlled trials of antihistamines for renal itch. lar relief of itch and pain with gabapentin and pregablin Anecdotal experience indicates that they are rarely if ever in HD patients [7] .
Nephron Clin Pract 2012;122:75–79 Rayner/Baharani/Smith/Suresh/Dasgupta 65.175.149.156 - 1/5/2014 4:01:06 AM Many patients reported improved sleep quality and of first choice based upon the results of a controlled trial mood, beyond that due to the relief of itching. This is [2] . Pregabalin may be effective in patients unable to tol-consistent with the demonstration of improved sleep erate gabapentin.
quality and reduction in depression due to gabapentin These treatments should be promoted widely amongst and pregabalin in HD patients with neuropathic pain the kidney community so that affected patients can be re- [13] .
lieved of this distressing and debilitating symptom.
Conclusions
Acknowledgements
Clinicians should enquire about skin irritation and The authors thank nursing staff in the HEFT nephrology ser- vice for identifying patients affected by itch: R. Adkins, M. Barrett, itching during consultations. Patients may be reluctant to A. Dodds, C. Rayney and C. Richardson.
admit to these symptoms due to embarrassment or a be-lief that they are caused by non-adherence to diet or phos-phate binder therapy.
Disclosure Statement
In patients with CKD and itching that persists despite attempts to correct calcium and phosphate balance and There are no financial conflicts of interest to declare. The au- treatment with emollient creams, gabapentin is the drug thors received no financial support for this study. References
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Neuropsychopharmacology (2003) 28, 694–703 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 Effect of Agomelatine in the Chronic Mild Stress Model ofDepression in the Rat Mariusz Papp*,1, Piotr Gruca1, Pierre-Alain Boyer2 and Elisabeth Mocae¨r2 Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland; 2Institut de Recherches Internationales Servier, Courbevoie Cedex,
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